Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D277/18—Nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
  • C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
  • C07D279/06—1,3-Thiazines; Hydrogenated 1,3-thiazines not condensed with other rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
  • C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
  • C07D279/08—1,3-Thiazines; Hydrogenated 1,3-thiazines condensed with carbocyclic rings or ring systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

• the present invention relates to 2-imino 1,3-thiazine derivatives. More specifically, the present invention relates to a 2-imino-1,3-thiazine derivative having a selective agonist or agonist action at the cannabinoid 2 receptor and a pharmaceutical use thereof.
• Cannabinoid was discovered in 1960 as the body of marijuana active substance, and its effects include central nervous system effects (hallucinations, euphoria, disturbed spatiotemporal sensations), and peripheral cell system effects (immunosuppression). , Anti-inflammatory, analgesic).
• cannabinoid 1 receptor As a cannabinoid receptor, the cannapinoid 1 receptor was discovered in 1990 and was found to be distributed in the central nervous system such as the brain, and its agonists suppressed the release of neurotransmitters, hallucinations, etc. Has a central effect. In 1993, a cannabinoid 2 receptor was discovered and found to be distributed in the immune system tissues such as the spleen, and its agonites suppressed immune system cells and inflammation. It has been shown to have immunosuppressive, anti-inflammatory and analgesic effects (Nature, 1993, 365, 61-65) o
• selective canonist or agonist cannabinoid 2 receptor Can avoid central nervous system side effects (such as hallucinations) derived from the cannapinoid 1 receptor, without causing addiction related to the cannapinoid 1 receptor, as well as immunosuppressants, anti-inflammatory drugs, Promising as an analgesic (Nature, 1998, 349, Compounds having cannabinoid 2 receptor agonist or agonist action include isoindolinone derivatives (W097 / 290) 79, WO 99/0 249 9), pyrazolyl derivatives (W098 / 4 15 19), etc. On the other hand, organophosphorus compounds having a 2-imino 1,3-thiazine skeleton are known.
• R 1 represents an optionally substituted alkylene
• R 2 is an alkyl
• R 1 represents an alkylene which may be substituted
• R 1 is a linear or branched alkylene having 2 to 9 carbon atoms which may be substituted with alkylene, a prodrug thereof, and a pharmaceutical product thereof. Or a salt thereof, or a solvate thereof,
• R 1 is a straight-chain alkylene having 2 to 9 carbon atoms substituted with alkylene, or a branched alkylene having 2 to 9 carbon atoms. Or a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.
• R 1 is 2,2-dimethyltrimethylene, 2,2-diethyltrimethylene, 2,2-ethylenetrimethylene, 1-methyltrimethylene, 2-methyltrimethylene, trimethylene, 2,2-di-n- Probilt trimethylene, 2,2—tetramethylene trimethylene, 2,2—pentamethylene trimethylene, 1,1 dimethylethylene or 1 methylethylene
• R 6 is methyl, ethyl, n—propyl, i -Propyl, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, methylthio, ethylthio, n-propylthio, i-
• a pharmaceutical composition comprising the compound according to any of 8) to 14) above, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof,
• a method for treating inflammation which comprises administering the pharmaceutical composition according to the above 1)
• 2 2) A method for immunosuppression comprising administering the pharmaceutical composition according to the above 1)
• 23 A method for treating nephritis, which comprises administering the pharmaceutical composition according to the above 1)
• Alkylene means a straight-chain or branched alkylene having 2 to 10 carbon atoms, for example, ethylene, 1-methylethylene, 1-ethylethylene, 1,1-dimethylethylene, 1,2 —Dimethylethylene, 1,1-Getylethylene, 1,2-Getylethylene, 1-Ethyl-2-methylethylene, Trimethylene, 1—Methyltrimethylene, 2-Methyltrimethylene, 1,1-Dimethyltrimethylene, 1,2— Dimethyltrimethylene, 2,2-dimethyltrimethylene, 1-ethyltrimethylene, 2-ethyltrimethylene, 1,1-getyltrimethylene, 1,2 —Jethyltrimethylene, 2,2-Jethyltrimethylene, 2-Ethyl-2-methylthiomethylene, tetramethylene, 1-methyltetramethylene, 2-methyltetramethylene, 1,1-dimethyltetramethylene, 1,2-dimethyltetramethylene, 2 , 2-dimethylte
• a linear or branched alkylene having 2 to 9 carbon atoms more preferably a branched alkylene having 2 to 9 carbon atoms is preferable.
• 2,2-dimethyltrimethylene, 2,2-getyltrimethylene, 1-methyltrimethylene, 2-methyltrimethylene, trimethylene, 2,2-di-n-provided rimethylene, 1,1-dimethylethylene, Or 1-methylethylene is preferred.
• These position numbers mean both the case where the numbers are assigned in the order of N—R 1 —S and the case that they are assigned in the order of S—R 1 —N.
• substituent of the “optionally substituted alkylene” examples include alkylene (eg, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, etc.) and cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentyl) , Alkoxy (eg, methoxy, ethoxy, etc.), alkylthio (eg, methylthio, ethylthio, etc.), alkylamino (eg, methylamino, ethylamino, dimethylamino, etc.), acylamino (eg, acetylamino, etc.), aryl ( For example, phenyl, etc., aryloxy (for example, phenoxy), halogen (fluorine, chlorine, bromine, iodine), hydroxy, amino, nitrite, alkylsulfonyl (for example,
• the alkylene substituted with alkylene includes alkylene substituted with alkylene via a spiro atom (for example, 2,2-ethylenetrimethylene, 2,2-trimethylenetrimethylene, 2,2-tetramethylenetrimethylene). , 2,2-pentamethylenetrimethylene, etc.) and alkylene substituted at different positions with alkylene (eg, 1,2-tetramethyleneethylene, 1,2-ethylenetrimethylene, etc.).
• 2,2-ethylenetrimethylene, 2,2-trimethylenetrimethylene, 2,2-tetramethylenetrimethylene, and 2,2-dimethylmethylenetrimethylene are preferred, and 2,2-ethylenetrimethylene is particularly preferred.
• Limethylene, 2,2-tetramethylene trimethylene, and 2,2-pentamethylene trimethylene are preferred.
• Alkyl means a linear or branched alkyl having 1 to 10 carbon atoms, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec— Butyl, t-butyl, n-pentyl, i-pentyl, neo-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.
• a linear or branched alkyl having 1 to 4 carbon atoms is preferable, and specifically, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-yl Butyl is preferred.
• Alkoxy means a group in which the above-mentioned “alkyl” is substituted on an oxygen atom, for example, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec—butoxy, t Monobutoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy, and n-hexyloxy.
• straight-chain or branched alkoxy having 1 to 4 carbon atoms is preferable, and methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, and t-butoxy are preferred.
• Alkylthio means a group in which the above “alkyl” is substituted on a sulfur atom, such as methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, i-butylthio, sec-butylthio, t-butylthio, n-pentylthio, n-hexylthio and the like.
• a straight-chain or branched alkylthio having 1 to 4 carbon atoms is preferable, and methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, i-butylthio, sec-butylthio, and t-butylthio are preferable.
• substituents of “optionally substituted amino” include alkyl (eg, methyl, ethyl, n-propyl, i-propyl, etc.) and acyl (eg, formyl, acetyl, propionyl, benzoyl, etc.). No. The nitrogen atom of the amino group may be mono- or di-substituted by these substituents.
• Amino which may be substituted includes amino, methylamino, ethylamino, n-propylamino, i-propylamino, dimethylamino, getylamino, ethylmethylamino, acetylamino, N-acetylmethylamino, propylmethylamino. Are preferred.
• Aryl means an aromatic carbocyclic group having 6 to 14 carbon atoms, and examples thereof include phenyl, naphthyl, anthryl and phenanthryl.
• “Aralkyl” means a group in which the above “alkyl” has been substituted by the above “aryl”, for example, benzyl, phenylethyl (eg, 1-phenylethyl, 2-phenylethyl), phenylpropyl (eg, 1-phenylethyl). Monophenylpropyl, 2-phenylpropyl, 3-phenylpropyl and the like; naphthylmethyl (eg, 1-naphthylmethyl, 2-naphthylmethyl and the like).
• Alkyloxy means a group in which the above “aralkyl” is substituted on an oxygen atom, such as benzyloxy, phenylethyloxy (for example, 1-phenylethyloxy, 2-phenylethyloxy), Phenylpropoxy (for example, 1 Monophenylpropyloxy, 2-phenylphenyloxy, 3-phenylpropyloxy, etc., naphthylmethoxy (eg, 1-naphthylmethoxy, 2-naphthylmethoxy, etc.) and the like.
• “Aralkylthio” means a group in which the above “aralkyl” is substituted on a sulfur atom, and includes, for example, benzylthio, phenylethylthio (for example, 1-phenylethylthio, 2-phenylethylthio), phenylpropylthio (for example, Examples thereof include 1-phenylpropylthio, 2-phenylpropylthio, 3-phenylpropylthio, etc., and naphthylmethylthio (eg, 1-naphthylmethylthio, 2-naphthylmethylthio, etc.).
• Alkylamino refers to a group in which one or two of the above “aralkyl” have been substituted on the nitrogen atom, for example, benzylamino, phenylethylamino (eg, 1-phenylethylamino, 2-phenylamino). Phenylethylamino, phenylpropylamino (eg, 1-phenylpropylamino, 2-phenylphenylamino, 3-phenylpropylamino), naphthylmethylamino (eg, 1-naphthylmethylamino) , 2-naphthylmethylamino), dibenzylamino and the like.
• Alkoxyalkyl means a group in which the above “alkyl” has been substituted by the above “alkoxy”, for example, methoxymethyl, ethoxymethyl, n-propoxymethyl, 1-methoxyl, 2-methoxyl, 1-ethoxyl N-Propoxychetil, 2-n-Propoxycill, 1-Methoxy-n-propyl, 2-Methoxy-n-propyl, 3-Methoxy-n-propyl, 1-1 Ethoxy n-propyl, 2-ethoxyethoxy n-propyl, 3-ethoxy n-propyl, 1-n-propoxy-n-propyl, 2-n-propoxy-n-propyl, 3-n-propoxy-n-propyl, etc. Is mentioned.
• Alkylthioalkyl means a group in which the above “alkyl” has been substituted by the above “alkylthio”, for example, methylthiomethyl, ethylthiomethyl, n-pro Pyrthiomethyl, 1-methylthioethyl, 2-methylthioethyl, 1-ethylthioethyl, 2-ethylthioethyl, 1-n-propylthioethyl, 2-n-propylthioethyl, 3-n-propylthioethyl, 1-methylthioethyl n-propyl, 2-methylthio-n-propyl, 3-methylthio-n-propyl, 1-ethylthio-n-propyl, 2-ethylthio-n-propyl, 3-ethylthio-n-propyl, 1-n-propyl, 2-n-propylthio-1-n
• the “optionally substituted aminoalkyl” means the above “alkyl” substituted by the above “optionally substituted amino”, and includes, for example, N-methylaminomethyl, N-acetylaminomethyl, N, N-dimethylaminomethyl and the like can be mentioned.
• Alkoxyalkoxy means the above “alkoxy” substituted by the above “alkoxy”, for example, methoxymethoxy, ethoxymethoxy, n-propoxymethoxy, isopropoxymethoxy, 1-methoxyethoxy, 2 —Methoxy ethoxy and the like.
• Alkylthioalkoxy means the above “alkoxy” substituted by the above “alkylthio”, and includes, for example, methylthiomethoxy, ethylthiomethoxy, n-propylthiomethoxy, isopropylthiomethoxy, 1-methylthioethoxy, 2-methyloxy And toxetoxy.
• Heteroaryl means a nitrogen atom, an oxygen atom, and / or a sulfur atom
• 5-benzimidazolyl dibenzofuryl, benzoxazolyl, quinoxalyl (eg, 2-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl), cinnolinyl (eg, 3-cinnolinyl, 4-cinnolinyl, 5-cinnoyl) Linyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl), quinazolyl (eg, 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 8-quinazolinyl), quinolyl (Eg, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), phthalazinyl (eg, 1-phthalazinyl, 5-quinolyl) Phthalazin
• heteroaryl of R 3 or R 4 3-pyridyl is particularly preferred.
• heteroaryl of R 7 2-phenyl is particularly preferred.
• Ring A means “optionally substituted aromatic carbocycle” or “optionally substituted aromatic heterocycle”.
• “Aromatic carbocycle” means an aromatic carbocycle having 6 to 14 carbon atoms, such as benzene, naphthalene, anthracene, and phenanthrene. Particularly, a benzene ring and a naphthylene ring are preferable.
• “Aromatic heterocyclic ring” means an aromatic ring having 1 to 9 carbon atoms containing 1 to 4 nitrogen atoms, oxygen atoms, and / or sulfur atoms, such as furan, thiophene, pyrrole, imidazole, and pyrazole.
• any position that can be substituted by these substituents may be substituted. Further, at the same or adjacent position on the ring, it may be substituted with alkylenedioxy.
• Aryloxy means a group in which the above “aryl” is substituted on an oxygen atom, For example, phenoxy, naphthoxy (eg, 1-naphthoxy, 2-naphthoxy, etc.), anthryloxy (eg, 1—anthroxy, 2—anthryloxy, etc.), phenanthyloxy (eg, 1-phenanthroxy, 2 — Phenanthyloxy, etc.).
• Cycloalkyl means cycloalkyl having 3 to 7 carbon atoms, and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
• Halogen refers to fluorine, chlorine, bromine and iodine. Particularly, fluorine, chlorine, and bromine are preferable.
• Haloalkyl means a group in which the above “alkyl” has been substituted by one or more halogens, for example, chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, chloroethyl (for example, 1-chloroethyl, 2-chloroethyl). And dichloroethyl (for example, 1,1-dichloroethyl, 1,2-dichloroethyl, 2,2-dichloromethyl), and the like.
• halogens for example, chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, chloroethyl (for example, 1-chloroethyl, 2-chloroethyl).
• dichloroethyl for example, 1,1-dichloroethyl, 1,2-dichloroethyl, 2,2-dichloromethyl
• Haloalkoxy means a group in which the above “alkoxy” has been substituted by one or more halogens, for example, dichloromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy (2,2,2-trifluroxy). Oloethoxy, etc.).
• substituent of the “optionally substituted carbamoyl” examples include alkyl (eg, methyl, ethyl, n-propyl, i-propyl, etc.), and acyl (eg, formyl, acetyl, propionyl, benzoyl, etc.).
• alkyl eg, methyl, ethyl, n-propyl, i-propyl, etc.
• acyl eg, formyl, acetyl, propionyl, benzoyl, etc.
• Can be The nitrogen atom of the carbamoyl group may be mono- or di-substituted by these substituents.
• rubumbamoyl N-methyl rubamoyl, N-ethylcarbamoyl and the like are preferable.
• Alkoxycarbonyl means a group in which carbonyl is substituted by the above “alkoxy”, and particularly preferred is methoxycarbonyl, ethoxycarbonyl and the like.
• Alkyl sulfiel means a group in which sulfyl is substituted by the above “alkyl”, and particularly preferred is methanesulfinyl, ethanesulfinyl and the like.
• Alkylsulfonyl means a group in which sulfonyl is substituted by the above “alkyl” group, and particularly preferred is methanesulfonyl, ethanesulfonyl and the like.
• Non-aromatic heterocyclic group means a non-aromatic ring having 1 to 9 carbon atoms containing 1 to 4 nitrogen atoms, oxygen atoms, and / or sulfur atoms, for example, 1-pyrolinyl, 2- Pyrrolinyl, 3-pyrrolinyl, pyrrolidino, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-a Midazolidinyl, 1-pyrazolinyl, 3-virazolinyl, 4-pyrazolinyl, 1-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, piperazino, 2-piperazini , 2-morpholinyl, 3-morpholinyl, morpholino, ,
• Alkoxyiminoalkyl means the above “alkyl” substituted by alkoxyimino. For example, methoxyminomethyl, ethoxyiminomethyl, 1-methoxyminoethyl and the like can be mentioned.
• R H is hydrogen, alkyl, optionally substituted ⁇ Li Lumpur, or optionally substituted non-aromatic heterocyclic group
• examples thereof include formyl, acetyl, benzoyl, toluoyl, and morpholinocarbonyl.
• cannabinoid 2 receptor agonism means that it exerts an agonist action on cannabinoid 2 receptor.
• the compound according to the present invention can be produced by the following steps.
• R 1 represents an optionally substituted alkylene
• R 2 is an alkyl
• the amino group of the compound represented by the formula (III) is converted into an isothiocyanate (isothiocyanate) to produce a compound represented by the formula (IV).
• the conversion method from an amino group to an isothiocyanate (isothiocyanate) is as follows: 1Ammonia (NH 3 , NH 40 H) ⁇ Disulfide in the presence of a base such as triethylamine (Et 3 N) carbon is not a Jichiokarubami de salt obtained by acting a (CS 2), black hole carbonate Echiru (C l C0 2 E t) , the method of treating with preparative Ryechiruamin (E t 3 N), the 2 the Jichiokarubami de salt , and a method to apply a method 4 Chio carbonyl diisopropyl formidacillin tetrazole exerting a method of processing a metal salt such as lead nitrate 3 Chiohosugen (CSC 1 2) and the like.
• a base 1.0 to 1.5 equivalents
• carbon disulfide 1.0 to 1.5 equivalents
• a non-protonic solvent eg, getyl ether, Stir for 0.5 to 10 hours in trihydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform.
• ethyl chlorocarbonate 1.0 to 1.5 equivalents
• triethylamine 1.0 to: L.5 equivalents
• the reaction temperature is preferably from 0 ° C to 100 ° C, particularly preferably from 0 ° C to room temperature.
• thiophosgene (1.0 to 1.5 equivalents) is added to compound (III), and a non-protonic solvent (for example, dimethyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform) is added. Stir for 0.5 to 10 hours.
• the reaction temperature is preferably from 0 ° C to 100 ° C, particularly 0 ° C to room temperature is preferred.
• thiocarbonyldimidazole (1.0 to 1.5 equivalents) is added to compound (III), and a non-protonic solvent (eg, dimethyl ether, tetrahydrofuran, dimethylformamide) is added. , Benzene, toluene, dichloromethane, chloroform, etc.) for 0.5 to 10 hours.
• the reaction temperature is preferably 0 ° (: up to 100 ° C, particularly preferably 0 ° C to room temperature.
• This step can be performed in a non-protonic solvent (eg, ethyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform, etc.).
• a non-protonic solvent eg, ethyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform, etc.
• the reaction temperature is preferably from 0 ° C to 100 ° C, particularly preferably from 0 ° C to room temperature, and the reaction time is preferably from 0.5 hour to 10 hours.
• NH 2 —R 1 —0 H R 1 is an optionally substituted alkylene may be used in an amount of 1.01.5 equivalents to compound (IV).
• NH 2 —R 1 —OH includes 2-aminoethanol, 2-amino-2-methylethanol, 2-amino-1-methylethanol, 2-amino-1,1-dimethylethanol, 3-aminopropanol, and 3 —Amino 22-dimethylpronol, 3-amino-1-methylpropanol, 3-amino-2-methylpropanol, 3-amino-3-methylpropanol, 3-amino-1 22-getylpropanol, 1-aminomethyl-1-hi Droxymethylcycloprone, 11-aminomethyl-1- (hydroxymethyl) cyclobutane, 2- (aminomethyl) cyclopentanol and the like.
• the ring closure method a method of treatment with 1 Jeffrey chill ⁇ zone dicarboxylate (D EAD) and Application Benefits Fueniruhosufi down (P h 3 P), and a method of treating the support with 2 hydrochloric can be mentioned up.
• a nonprotonic solvent eg, ethyl acetate, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform, etc.
• a nonprotonic solvent eg, ethyl acetate, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform, etc.
• DEAD diethyl azodicarboxylate
• Ph3P triphenylphosphine
• R 7 is a step of manufacturing a compound represented by the formula (II).
• R 5 represents 0 or S
• R 6 is alkyl, alkoxy, alkylthio, optionally substituted amino, optionally substituted aralkyl oxy, optionally substituted aralkylthio, substituted Represents an optionally substituted aralkylamino, alkoxyalkyl, alkylthioalkyl, or an optionally substituted aminoalkyl
• R 7 is alkyl, an optionally substituted amino, an optionally substituted aryl, or a substituted Represents an optionally substituted heteroaryl
• a base for example, triethylamine, pyridine, N, N-dimethylaminopyridine, etc.
• X has the same meaning, and X represents a halogen.
• the reaction may be carried out in accordance with the usual N-acylation conditions.
• a non-protonic solvent for example, diethyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform, etc.
• the reaction may be performed at 0 ° C.
• a compound of a dithioic acid ester in which R 5 is S and R 6 is alkylthio or aralkylthio which may be substituted is obtained by converting carbon disulfide (CS 2 ) in the presence of a base (for example, sodium hydride or the like). It can also be obtained by reacting and then reacting with an alkyl halide (eg, methane, ethane, etc.) or an aralkyl halide (eg, benzyl bromide, etc.).
• a non-protonic solvent eg, diethyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform, etc.
• the solvent at 0 ° C to room temperature can be used. The reaction proceeds.
• R 2 is a group represented by the following formula: —S ⁇ 2 R 7 (where R 7 is alkyl, substituted or unsubstituted amino, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaryl)
• R 7 S ⁇ 2 X wherein, X may be a compound represented by the formula (VI) in the presence of a base.
• Prodrugs are compounds that are pharmaceutically active compounds of the present invention in vivo under physiological conditions. Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985.
• the prodrug of the compound according to the present invention can be produced by introducing a leaving group into a substituent (for example, amino, hydroxy, etc.) on the A ring to which a leaving group can be introduced.
• a leaving group for example, amino, hydroxy, etc.
• Examples of prodrugs of an amino group include olebamates (eg, methyl olebamate, cyclopropylmethyl carbamate, t-butyl carbamate, benzyl carbamate, etc.), amides (eg, formamide, acetamide, etc.), N— And alkyl forms (for example, N-arylamine, N-methoxymethylamine, etc.).
• hydroxy group prodrug examples include an ether form (eg, methoxymethyl ether, methoxetoxymethyl ether), an ester form (eg, acetate, pivaloate, benzoate, etc.).
• Pharmaceutically acceptable salts include, as basic salts, for example, sodium salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts; Aliphatic aliphatic amine salts such as trimethylamine salt, tritylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, procaine salt; aralkylamine salts such as N, N-dibenzylethylenediamine; Heterocyclic aromatic amine salts such as pyridine salt, picoline salt, quinoline salt and isoquinoline salt; tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylam
• the acidic salt examples include inorganic salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, and perchlorate; acetate, propionate, lactate, and maleate. , Fumarate, tartrate, phosphate, citrate, ascorbate; organic acid salts; methanesulfonate, isethionate, benzenesulfonate, P-toluenesulfonate, etc. Sulfonates; acidic amino acids such as aspartate and glutamate;
• the solvate means a solvate of a compound represented by the formula (I) or (II), a prodrug thereof, or a pharmaceutically acceptable salt thereof. Examples include solvates, monohydrates, dihydrates and the like.
• the compound of the present invention has an affinity for the cannapinoid 2 receptor (CB 2 R), selectively binds to the cannabinoid 2 receptor (CB 2 R), and has a CB 2 R antagonist action or a CB 2 R agonist. Show action. In particular, it exhibits a CB 2 R agonist effect.
• the compound of the present invention has no affinity for cannapinoid 1 receptor (CB 1 R) and avoids central nervous system side effects (such as hallucinations) derived from cannabinoid 1 receptor (CB 1 R). And does not trigger the dependence associated with the cannapinoid 1 receptor (CB1R).
• the compound of the present invention can be used for the treatment or prevention of diseases involving cannabinoid 2 receptor (CB 2 R).
• CB 2 R cannabinoid 2 receptor
• CB2 R cannabinoid 2 receptor
• the European Journal of Pharmacology 396 (2000) 85-92 describes that the CB2 receptor gonist has an analgesic effect.
• the compound of the present invention is considered to suppress the activation of immune system cells and inflammatory cells and to exert peripheral cell system actions (immunosuppressive, anti-inflammatory, analgesic actions), Agent, therapeutic agent for immunodeficiency, immunosuppressant, immunomodulator, therapeutic agent for autoimmune disease, rheumatoid arthritis, multiple sclerosis, etc.
• cannapinoid 2 receptor agonists have an inhibitory effect on rat Thy-1 antibody-induced nephritis (W097 / 29079), and as a therapeutic agent for nephritis. Is also useful.
• the pharmaceutical composition containing the compound of the present invention can take a dosage form for oral and parenteral administration. That is, oral preparations such as tablets, capsules, granules, powders, and syrups, or solutions or suspensions for injection such as intravenous injection, intramuscular injection, and subcutaneous injection, inhalants, eye drops, nasal drops, and suppositories. Preparations or parenteral preparations such as transdermal preparations such as ointments. These preparations can be manufactured using suitable carriers, excipients, solvents, bases and the like known to those skilled in the art.
• the active ingredient and the auxiliary ingredient are compressed or molded together.
• Supplementary ingredients include pharmaceutically acceptable excipients, such as binders (eg, corn starch), fillers (eg, lactose, microcrystalline cellulose, etc.), disintegrants (eg, For example, sodium starch glycolate or a lubricant (eg, magnesium stearate) is used. Tablets may be coated as appropriate.
• binders eg, corn starch
• fillers eg, lactose, microcrystalline cellulose, etc.
• disintegrants eg, sodium starch glycolate or a lubricant (eg, magnesium stearate) is used. Tablets may be coated as appropriate.
• suspending agents eg, methylcellulose, etc.
• emulsifiers eg, lecithin, etc.
• preservatives and the like are used.
• preparations for injection they may be in the form of solutions, suspensions or oily or aqueous emulsions, which may contain suspension stabilizers or dispersants.
• an inhalant it should be an ophthalmic solution as a liquid that can be used in inhalers. Also used as a liquid or suspending agent.
• the dose of the compound of the present invention varies depending on the administration form, patient condition, age, weight, sex, or concomitant drug (if any), and is ultimately left to the judgment of a physician.
• M e methyl
• E t ethyl
• P r> propyl
• P r 1 i-propyl
• B u butyl
• B u 1 i - butyl
• B u s sec - butyl
• Extract solution is sulfuric anhydride
• the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (n-hexane Z-ethyl acetate) to give 2- (2-isopropylphenyl) imino-3-propionate.
• 2,5-Dimethyl-1,3-thiazine (0.18 g, yield 56%) was obtained as a colorless oil.
• the compounds of the present invention also include the compounds shown in the following table. These compounds can be synthesized in the same manner as in the above Examples. The number in the left column in the table represents the compound No.

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